Mechanobiology of Inflammation in the Intervertebral Disc

项目概要： 椎间盘退变（IVD）引起的残疾和疼痛影响了超过40%的美国人， 每年花费超过1000亿美元。IVD变性（DD）的病因尚不清楚。有 临床上需要更好地了解DD的机制， 直接治疗IVD、缓解DD和促进脊柱功能恢复的方法。 我 炎症是椎间盘源性疼痛的关键因素。高迁移率族蛋白1（ HMGB1蛋白是一种 一种普遍存在的核蛋白，由应激或死亡细胞分泌到细胞外。生物 HMGB1的功能取决于其细胞位置、氧化还原状态和结合伴侣。最近的研究 显示HMGB1水平随DD严重程度增加而增加，尽管HMGB1在细胞核中的生物学功能 髓（NP）细胞及其在DD中的作用在很大程度上是未知的。HMGB1对NP细胞的作用 机械生物学也同样未知，可能与促炎潜力双重相关， 二硫键HMGB1和完全还原的HMGB1的趋化活性。的目的 提出的研究是鉴定HMGB1在DD中的氧化还原依赖性功能。我们的全球假设 HMGB1将触发IVD促炎信号传导，促进ECM降解并改变NP 细胞机械生物学的氧化还原依赖的方式。目标1研究将量化生物学和 HMGB1在人NP细胞中氧化还原亚型的机械转导功能。我们还将确定 介导促炎和机械生物学活性的特异性结合受体 NP细胞中的HMGB1亚型。目的2研究将确定HMGB1作为中枢神经系统的贡献。 介导DD炎症和机械生物学中的损伤相关分子模式（DAMP） 从急性期到慢性期。这些研究将提供机械证据， HMGB1的氧化还原亚型有助于DD和机械转导。我们的发现可能会发现 缓解DD发生或进展的目标。由于多种HMGB1亚型有可能 为了改变NP细胞的细胞骨架，从而改变NP细胞的机械生物学，我们预测我们的研究将确定 减轻IVD机械转导改变的策略，比 调节炎症信号。

Project Summary: Disability and pain stemming from degenerated intervertebral discs (IVD) affects over 40% of U.S adults and costs >$100 billion annually. The etiology of IVD degeneration (DD) is unknown. There is a significant clinical need for a better mechanistic understanding of DD, and for therapeutic approaches that directly treat the IVD, mitigate DD, and promote recovery of spine function. I nflammation is a key contributor to discogenic pain. High mobility group box 1 ( HMGB1) protein is a ubiquitous nuclear protein that is secreted extracellularly by stressed or dying cells. The biologic function of HMGB1 depends on its cellular location, redox state, and binding partners. Recent studies show that HMGB1 levels increase with DD severity, though the biologic function of HMGB1 in nucleus pulposus (NP) cells and its role in DD are largely unknown. The contributions of HMGB1 to NP cell mechanobiology are similarly unknown, and may be dually related to the pro-inflammatory potential of disulfide HMGB1 and to the chemotactic activity of fully reduced HMGB1. The objective of the proposed studies is to identify the redox dependent function of HMGB1 in DD. Our global hypothesis is that HMGB1 will trigger IVD pro-inflammatory signaling, promote ECM degradation and alter NP cell mechanobiology in a redox dependent manner. Aim 1 studies will quantify the biological and mechanotransduction function of redox isoforms of HMGB1 in human NP cells. We will also identify the specific binding receptors that mediate the pro-inflammatory and mechanobiological activity of HMGB1 isoforms in NP cells. Aim 2 studies will identify the contribution of HMGB1 as a central mediating damage associated molecular pattern (DAMP) in DD inflammation and mechanobiology from acute to chronic stages in vivo. These studies will provide mechanistic evidence about how redox isoforms of HMGB1 contribute to DD and mechanotransduction. Our findings may identify targets for mitigating DD initiation or progression. Since multiple HMGB1 isoforms have the potential to alter the cytoskeleton and thus mechanobiology of NP cells, we predict that our studies will identify strategies for mitigating alterations in IVD mechanotransduction, which are more extensive than regulating inflammatory signaling.